Device for intranasal administration

ABSTRACT

Disclosed herein are devices and processes for preparing a vial for an intranasal administration of a medicament where the vial comprises reduced oxygen content.

FIELD OF THE INVENTION

Disclosed herein are vials and methods for preserving a ketorolaccomposition where each vial comprises a head space with reduced oxygencontent.

BACKGROUND

Ketorolac has been known for several years (U.S. Pat. No. 4,089,969) andis used in human therapy as an analgesic and an anti-inflammatory as thetromethamine salt. U.S. Pat. No. 4,089,969 is incorporated herein byreference in its entirety.

Ample literature is available on ketorolac (for instance, “Ketorolac—Areview of its pharmacodynamic and pharmacokinetic properties and itstherapeutic potential”, Drugs 39(1): 86-109, 1990). It is described as adrug with considerably higher analgesic activity than many othernon-steroidal anti-inflammatory drugs. Most significantly, it hasanalgesic activity comparable to that of the opiates, such as morphine,without the well-known side effects of the latter.

It is known that ketorolac can be formulated as a nasally administrablecomposition. See U.S. Pat. No. 6,333,044 to Recordati, and U.S. PatentApplication Publication No. 2009/0042968, which are incorporated hereinby reference in their entirety.

Administering ketorolac tromethamine nasally has certain advantages overadministering the compound by injection or orally. These are discussedin prior art references U.S. Pat. No. 6,333,044 and U.S. PatentPublication 2009/0042968. The latter reference teaches that ketorolactromethamine is successfully combined with a local anesthetic, e.g.lidocaine hydrochloride, to reduce the stinging effect that somepatients experience with the nasal administration of ketorolactromethamine alone.

SUMMARY OF THE INVENTION

In one aspect, this invention provides a vial capped with a spraysystem, the vial comprising: a solution, a dip tube attached to thespray system and dipping into the solution, and a head space above thesolution, wherein the head space comprises no more than about 10% v/voxygen.

In another aspect, this invention provides a nasal spray device,comprising: a vial and a nasal spray system capped to the vial whereinthe vial comprises a solution, a dip tube attached to the nasal spraysystem and dipping into the solution, and a head space above thesolution, wherein the head space comprises no more than about 10% volumeto volume (v/v) oxygen.

In still another aspect, this invention provides a high recovery vialcapped with a spray system, comprising a concave or V shaped innerbottom. In some embodiments, the high recovery vial further comprises ahead space above the solution, wherein the head space comprises equal toor less than about 10% v/v oxygen.

These and the other embodiments are further described in the text thatfollows.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be further described with reference being made tothe accompanying drawings.

FIG. 1 illustrates an example of a vial, preferably with a head spacecomprising equal to or less than about 10% v/v oxygen.

FIG. 2 illustrates an example of a high recovery vial, preferably with ahead space comprising equal to or less than about 10% v/v oxygen.

FIG. 3 illustrates an example of a conventional oxygen reduction device.

FIG. 4 illustrates a tube used in the conventional oxygen reductiondevice.

FIG. 5 illustrates a tube used in the improved oxygen reduction device.

FIG. 6 illustrates an example of frequency modulation signals fromoxygen absorption. The peak to peak amplitude of each spectrum isproportional to oxygen concentration (noted to the right of each scan).These spectra were taken through 1″ diameter glass containers filledwith certified gas mixtures of oxygen in nitrogen.

DETAILED DESCRIPTION OF THE INVENTION

Before the various aspects of this invention are described, it is to beunderstood that the invention is not limited to the particularmethodologies, protocols, and reagents described, as these may vary. Itis also to be understood that the terminology used herein is intended todescribe particular embodiments of the present invention, and is in noway intended to limit the scope of the present invention as set forth inthe appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All technical and patentpublications cited herein are incorporated herein by reference in theirentirety. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “about” when used before a numerical designation, e.g., pH,temperature, amount, concentration, and molecular weight, includingrange, indicates approximations which may vary by (+) or (−) 5%, 1% or0.1%.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a pharmaceutically acceptable salt”includes a plurality of pharmaceutically acceptable salts, includingmixtures thereof.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions and methods include the recited elements, but notexcluding others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) of the claimed invention.“Consisting of” shall mean excluding more than trace amount of elementsof other ingredients and substantial method steps. Embodiments definedby each of these transition terms are within the scope of thisinvention.

“Ketorolac” refers to the chemical compound of5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid which has thefollowing Formula (I):

or a pharmaceutically acceptable salt thereof

For purposes of this application, the name ketorolac encompassesindividually or collectively the racemic mixture, a scalemic (orenantiomerically enriched) mixture, or optically active compound as wellas tautomers thereof, and includes the pharmaceutically acceptable saltsof ketorolac, particularly the tromethamine salt. As used herein, aracemic mixture of ketorolac is a mixture having equal amounts of thetwo enantiomers of Formula (I). A scalemic or enantiomerically enrichedmixture of ketorolac is a mixture where the amount of one of theenantiomers of Formula (I) is larger than the other enantiomer. Anoptically active compound may include enantiomerically enriched orenantiomerically pure compound. Enantiomerically pure compound refers toketorolac having more than 99%, e.g. 99.5%, or 99.9% of one of theenantiomers relative to the total amount of ketorolac.

“Lidocaine” refers to the chemical compound of2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide, which has the Formula(II):

or a pharmaceutically acceptable salt thereof.

Many pharmaceutically acceptable salts of lidocaine are known.Non-limiting examples of such salts are lidocaine hydrochloride andlidocaine methanesulphonate. As used herein, the term “lidocaine” refersto the compound or any of its pharmaceutically acceptable salts, unlessotherwise indicated.

The term “subject,” “individual” or “patient” is used interchangeablyherein, and refers to a human.

The term “pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only, sodium,potassium, calcium, magnesium, ammonium, tromethamine andtetraalkylammonium, and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate (methanesulfonate),acetate, maleate, and oxalate. Suitable salts include those described inP. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of PharmaceuticalSalts Properties, Selection, and Use; 2002.

Device

One aspect of this invention is a device, such as a vial, comprising avolume of about 10 mL or less associated with a spray system fordelivering a medicament to a subject from a solution containing themedicament. Such a vial will generally be capped with the spray systemand will have a headspace between the surface of the solution and thecap. We have found that the content of the gas occupying the headspaceabove the solution where the medicament is ketorolac need to be keptbelow 10% v/v oxygen to ensure the long term stability of the ketorolacsolution without the need of refrigeration.

Our ambient atmosphere (air) contains about 20% v/v oxygen, 78%nitrogen, 1% argon, and a number of other components. It has been foundthat high oxygen content can degrade certain medicament solutions (e.g.ketorolac tromethamine) in the vial thereby reducing the shelf life ofthe medicament. Under such circumstances, the solution-containing vialis often kept refrigerated to maintain stability of the solution overthe desired shelf life of the product. The need for refrigeration canincrease the cost of handling and storing of the product.

We have found that ketorolac can produce several degradation products,such as the 1-keto analog having Formula (III) and the chemical name of5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one (or5-benzoyl-1-keto-2,3-dihydro 1H-pyrrolizine, in racemic or opticallyactive form), in solution.

The 1-keto analog forms when ketorolac is oxidized by too much oxygen inthe headspace of the device. We have found that the formation of the1-keto analog is especially problematic for the intranasal compositionswith a high concentration of ketorolac. Prior to the discovery ofintranasally administered ketorolac, it has been available forparenteral administration at a much lower concentration in the order ofabout 3% or 1.5% or less. A lower concentration is used because a largervolume can be administered over time. At this lower concentration, theamount of 1-keto analog formed is within an acceptable level. However,due to the limited volume that can be administered intranasally, a muchhigher concentration of ketorolac is required, which we found can resultin a concentration of the 1-keto analog that can be outside theacceptable level, which may cause safety concerns. It has beendiscovered that by ensuring that there is less than 10% v/v oxygen inthe head space of the vial containing a highly concentrated ketorolactromethamine solution, the shelf life of the final product is extendedwithout the need for refrigeration. The unique product of this inventionmay be obtained by a manual process, as discussed hereinafter, or by aunique oxygen reduction device provided herein that reduces the level ofoxygen content in the vial containing the intranasal formulation therebyreducing the level of the ketorolac degradative products and resultingin a device providing a level of stability that allows the formulationto be stored at room temperatures for two years or more.

The ketorolac solution for intranasal administration is contained andstored in a container, referred to herein as a vial. Owing to a limitedvolume of the solution in the vial, there is often head space left inthe vial. Typically, this head space is filled with air having about 20%v/v oxygen. In many cases, it is not practical to reduce the head spacevolume to an extent that the amount of air is not a substantial issue tothe stability of the medicament inside the vial. In most cases, the headspace increases as the medicament is expelled from the vial. Forexample, in the case of a vial containing an intranasal composition, thehead space volume is typically determined by the following factors:

-   -   (1) The size of the vial: Due to the presence of the spray        system on the vial in order to deliver the composition by        intranasal spray, the minimum size of the vial needs to be able        to balance the weight of the spray system in order to stabilize        the vial when the vial is stored. If the vial is too small, the        vial will tend to tip over and fall due to the weight of the        spray system. Preferably the minimum volume of the vial is about        3.5 mL. Preferably, the maximum volume of the vial is about 10        mL, more preferably 5 mL.    -   (2) The volume of the composition inside: In a preferred        embodiment, the amount of drug solution that may be contained in        a single vial is about 0.4-4 mL; more preferably about 0.6-3 mL;        and even more preferably about 0.8-2 mL. In one embodiment the        volume is about 1 mL and up to about 1.8 mL. In another        embodiment the volume is not less than about 1.6 mL and up to        about 1.8 mL.

Accordingly, the minimum head space is dictated by the size of the vialand the volume of the solution contained therein and generally about 1mL, 3 mL, 4 mL or larger, which, if filled with air will contain anoxygen amount that may cause significant degradation of the drugcontained in the vial. Generally, the headspace is no more than 80% ofthe total volume of the vial.

Thus it can be seen that the invention, based on this line ofdiscoveries and observations of the inventor, comprises several aspects.One aspect is a product for nasal administration of a solution ofketorolac, and optionally lidocaine, which is contained in a vial fittedwith an atomizer and having a headspace that contains less than 10% v/voxygen. Another aspect of this invention is a method of administeringketorolac, alone or in combination with lidocaine, by nasaladministration using the product. Another aspect of the invention is amethod of making the product of the invention by placing a solution ofketorolac, and optionally lidocaine, into a vial containing a suitableamount of the solution for nasal administration, ensuring that theheadspace of the vial has less than 10% v/v of oxygen, and capping thevial. Still another aspect of the invention is a system for treatingpain or inflammation in a human that comprises the product incombination with labeling instructions for such use. Other aspects ofthe invention will apparent to one of ordinary skill in the art uponreading this application in its entirety.

Accordingly, in one aspect, there is provided a vial capped with a spraysystem, the vial comprising: a solution, a dip tube attached to thespray system and dipping into the solution, and a head space above thesolution, wherein the head space comprises equal to or less than about10% v/v oxygen.

An example of the vial capped with a spray system, is illustrated inFIG. 1. The vial 100 in FIG. 1 is shown for illustration purposes onlyand it is to be understood that any variation in the size, shape, ordesign of the vial is well within the scope of the present invention.The vial 100 may be made of glass, polymer, or any other suitablematerial known in the art. The vial 100 comprises a cap 101 which is aspray system. In some embodiments, the spray system is a nasal spraysystem. In some embodiments, the nasal spray system is a metered nasalspray system.

The vial 100 comprises a solution 102 in the vial. In some embodiments,the solution 102 is a medicament. In some embodiments, the medicamentcomprises a ketorolac solution as described in one or more of U.S. Pat.No. 6,333,044, U.S. Patent Application Publication No. 2009/0042968,U.S. Provisional Application No. 61/061,522, filed on Jun. 13, 2008,titled, “Unit Dose Formulations of Ketorolac and Lidocaine Combinationfor Intranasal Administration,” and U.S. Provisional Application No.61/______, filed on even date herewith as Attorney Docket No.056369-1752 and entitled, “Unit Dose Formulations of Ketorolac forIntranasal Administration,” all of which are incorporated herein byreference in their entirety. In some embodiments, the vial containsmultiple unit doses of the ketorolac solution. In some embodiments, thevial contains up to 8 unit doses of the ketorolac solution.

The vial 100 comprises a dip tube 103 in the vial that is attached tothe spray system at one end and is dipping in the solution at the otherend. The vial 100 also comprises a head space 104 in the vial where thehead space comprises an inert gas with no more than about 10% v/voxygen. In some embodiments, the head space comprises an inert gas withno more than about 8% v/v oxygen; or more preferably no more than about5% v/v oxygen. In some embodiments, the head space comprises an inertgas having between about 5% to about 10% v/v oxygen; or between about 3%to about 8% v/v oxygen; or between about 2% to about 5% v/v oxygen.

Keeping the percentage of oxygen the head space to 10% or less keeps thesolution stable for about two years. It is to be understood that“stable” describes a state that the solution remains substantiallyunchanged in the percentage of active ingredient in solution so that itis suitable for its intended use during the relevant period of time. Forexample, if the solution is a medicament, the solution is in a stablestate if it meets the standard for being used as a medicament asrequested by a New Drug Application applicant and required by therelevant regulatory agency, such as the United States Food and DrugAdministration. Thus, a stable solution may comprise certain minordegree of degradation, so long as the degree of degradation is notsignificant enough to make it unusable for its intended use, e.g., fallbelow the standard for use as a medicament. In some embodiments, thesolution in the vial can be stored in the vial for about two years atroom temperature. In some embodiments, no more than about 10% v/v oxygenin the head space increases the shelf life of the solution as comparedto the vial containing an ambient atmosphere. Where the vial containshighly concentrated ketorolac solution, e.g., 12-38% or 15-35% w/v,storing the ketorolac composition under a gaseous atmosphere that hasreduced oxygen content, for example, no more than about 10% v/v ofoxygen, allows the composition to be stored at room temperatures for asufficiently long period of time, such as two years, without significantdegradation.

A regularly shaped vial, such as the one shown in FIG. 1, has asubstantially flat inner bottom. Further, there is typically a spacebetween the tip of the dip tube and the bottom of the vial to allowliquid to flow into the dip tube. This presents multiple issues such asthe need to use excess solution to ensure that adequate amounts can bedelivered in each dosing for a multiple dose container as well aspotential introduction of air into the dip tube thereby providing lessthan the desired dose. In another embodiment of this invention, there isprovided a high recovery vial for nasal spray which reduces thelikelihood of air being introduced into the dip tube duringadministration while also reducing the amount of solution required toprovide adequate dosing. High recovery vials are especially beneficialwhere the drug composition is expensive. FIG. 2 illustrates an exampleof a high recovery vial 200. As shown in FIG. 2, the inner bottom of thehigh recovery vial 200 comprises a concave or “V” shaped bottom 201 sothat residue drug solution (represented by the dashed line 202, whilethe dashed line 203 represents the amount of drug solution prior to use)is collected in the tip of the concave or “V” shaped bottom 201. Thevial also comprises a dip tube 204 having a notch 205 to allow thesolution to go into the dip tube 204. In one embodiment, the dip tube isa stiff-notched dip tube. The vial comprises a head space 104, whichpreferably has less than 10% v/v oxygen.

In another aspect, there is provided a nasal spray device, comprising: avial having a volume of no more than 10 mL and a nasal spray systemcapped to the vial wherein the vial comprises a solution, a dip tubeattached to the nasal spray system and dipping into the solution, and ahead space above the solution, wherein the head space comprises no morethan about 10% v/v oxygen. In some embodiments, the nasal spray devicecomprises the vial as described above. In preferred embodiments, theamount of oxygen in the head space is as provided above. A nasal spraydevice is one designed for the exit tip to be inserted into a patient'snostril to spray a defined amount of the solution into the nostril.

In some embodiments, the nasal spray device is further equipped with ametering chamber to measure a desired amount of the composition to besprayed into the patient's nasal passage. In one embodiment, themetering chamber is coupled with the spraying device so that a patientcan simultaneously measure and spray a desired amount (e.g. a unit dose)of the composition. In one embodiment, the metering chamber is able todeliver a predetermined amount of about 50 to about 125 microliters ofliquid. In one embodiment, the metering chamber is able to deliver fromabout 50 to about 100 microliters of liquid. In one embodiment, themetering chamber having different volume deliveries can be used. In oneembodiment, the metering chamber is able to measure about 50 microlitersof liquid. In one embodiment, the metering chamber is able to measureabout 100 microliters of liquid. Appropriate vials and spray deviceswith or without a metering chamber are available to one of skill in theart by referring to “Remington's Pharmaceutical Sciences.” One sourcefor such vessels is Ing. Erich Pfeiffer GmbH, Radolfzell, Germany.Another source is Valois, 50 avenue de l'Europe, 78164 MARLY-LE-ROI,France.

In another aspect, the vial or nasal spray device of this invention isin combination with labeling instructions for use in treating a pain orinflammation in a human subject. In some embodiments, the pain is theresult of a trauma inflicted on the subject. In some embodiments, thepain is the result of a medical operation performed on the subject. Insome embodiments, the pain is pathological. In some embodiments, thepain is neuropathic. In some embodiments, the pain is migraine or otherheadache pain.

Methods and Processes

In yet another aspect, there is provided a method of preparing a nasalspray device, the nasal spray device comprising: a vial having a volumeof no more than 10 mL and a nasal spray system capped to the vialwherein the vial comprises a solution, a dip tube attached to the nasalspray system and dipping into the solution, and a head space above thesolution, the process comprising:

a) adding a pharmaceutical composition susceptible to degradation byoxygen;

b) flowing an inert gas into the vial to purge the air out of the vial;and

c) capping the vial with a nasal spray system,

wherein the process results in an oxygen content in the head space ofthe vial equal to or less than about 10% v/v oxygen after the capping ofthe vial with the nasal spray system.

In some embodiments, the inert gas is nitrogen. In some embodiments, theinert gas is a noble gas, such as argon.

The following describes an efficient process to purge air from thevials, especially in a contemplated manufacturing context.

In a conventional manufacturing facility, an oxygen reduction device300, as shown in FIG. 3, is used for purging air out of a vialcontaining a solution before capping of the vial, for example 100 or200, with, for example, a cap or a spray system. In order to purge airout of the vial, a stream of an inert gas, such as argon or nitrogen,may be passed over the vial using a tube 301, also referred to as purgebar, attached to the oxygen reduction device 300. The tube 301 asattached to the oxygen reduction device 300 can be seen partially inFIG. 3.

This tube 301 is illustrated fully in FIG. 4. The tube 301 comprises aninlet 401 and an outlet 402 and a number of holes 403 at various pointsin the tube 301. The nitrogen enters from the inlet 401 and passesthrough the tube 301 to exit through outlet 402. It is to be understoodthat the inlet 401 and outlet 402 can be interchanged depending on theconfiguration of the attached tube 301 with the oxygen reduction device300. The holes 403 pass a stream of inert gas, such as nitrogen orargon, over the vials. Typically, in a manufacturing process, nitrogenis preferred due to cost consideration. However, the holes 403 pass theinert gas around the vials and not into the vials. Additionally, thetube 301 is attached to the oxygen reduction device 300 in such a waythat the inert gas may not pass directly into the mouth of the vials butmay instead be around them. In the case of nitrogen, this diffusion ofthe nitrogen around the vials is further coupled with the fact that thenitrogen being lighter than the air will not replace the air in thevials. This can lead to the incomplete purging of the air from thevials. This incomplete purging may be more pronounced in an asepticenvironment due to rapid air flow in that situation. After the laststation, where a lid or a spray system is snapped on the vial to cap thevial, a significant amount of air may remain in the vial which may leadto the degradation of the solution, such as a medicament, in the vial.

In one aspect, there is provided an improved oxygen reduction device forpurging air from a vial where the vial comprises a solution and a headspace, the improved oxygen reduction device comprises a tube with one ormore purging outlets that flow an inert gas such as nitrogen directlyover and into the vial to purge the air out of the vial, although otherinert gases such as argon can be used. The following description usesnitrogen to illustrate the device and process for brevity.

The tube 500 in the improved oxygen reduction device 300 is asillustrated in FIG. 5. The tube 500 comprises an inlet 401 and an outlet402. The nitrogen enters from the inlet 401 and passes through the tube500 to exit through outlet 402. It is to be understood that the inlet401 and outlet 402 can be interchanged depending on the configuration ofthe attached tube 500 with the oxygen reduction device. The tube 500optimally may comprise two brackets 501 and 502 for attaching the tube500 to other components of the oxygen reduction device 300. The tube 500comprises one or more purging outlets 503 (also called bar nozzles) thatdirect the nitrogen directly on the mouth of the vial therebyeffectively purging the air out of the vial. FIG. 5 comprises four suchpurging outlets 503 which is for illustration purposes only. It is wellunderstood that the number of the purging outlets 503 can vary dependingon, for example, the oxygen reduction device 300 and the length of theassembly line carrying the vials along the device, etc. It is also to beunderstood that the design of the tube 500, inlet 401 and outlet 402,brackets 501 and 502 and purging outlets 503 in FIG. 5 is forillustration purposes only. It is contemplated that the purging outlet503 can have different configurations so long as it can deliver nitrogendirectly onto the mouth of the vial. It is also contemplated that thelength and size of the purging outlet 503 and/or the position of thevial may be adjusted so that the distance between the tip of the purgingoutlet 503 and the mouth of the vial can be optimal for deliveringnitrogen inside the vial.

In some embodiments, the tube 500 has at least two purging outlets 503.In some embodiments, the tube 500 has at least three purging outlets503. In some embodiments, the tube 500 has four purging outlets 503. Thetube 500 can be made of materials well known in the art. For example,the tube 500 can be made of stainless steel. In some embodiments, thetube 500 is made of plated metal. It is important that the purgingoutlets 503 are oriented in such a manner that the distal end of thepurging outlet 503 is placed over the mouth of the vial. In someembodiments, at least one purging outlet 503 of the tube 500 is close toa last station where a capping of the vial with the spray system takesplace in order to minimize oxygen reentry into the gaseous atmosphere inthe vial. The orientation of the purging outlet 503 should be combinedwith a capping system such that capping occurs within 1 second ofpurging and preferably within 0.6 seconds of purging and even morepreferably from 0.3 seconds to 0.5 seconds, and most preferably 0.4second.

The one or more purging outlets 503 of the tube 500 in the oxygenreduction device 300, as illustrated in FIG. 5, flow nitrogen directlyover and into the vial to purge the air out of the vial thereby reducingan oxygen content in the head space of the vial to equal to or less thanabout 10% v/v oxygen. In some embodiments, the reduction in the oxygencontent in the head space of the vial to equal to or less than about 10%v/v oxygen is an improvement over a conventional oxygen reduction devicewherein the reduction in the oxygen content in the head space of thevial is more than about 10% v/v oxygen. In some embodiments, thereduction in the oxygen content in the head space of the vial is equalto or less than about 8% v/v oxygen; equal to or less than about 5% v/voxygen. In some embodiments, the reduction in the oxygen content in thehead space of the vial is in the range of about 5-10%, 3-8% or 2-5% v/v.

In some embodiments, the improvement in the oxygen reduction devicefurther comprises adjusting a flow rate of the nitrogen to reduce theoxygen content in the vial. The flow rate of the nitrogen can beincreased or decreased depending on the purging of the air out of thevial. This adjustment of the nitrogen flow can help reduce the oxygencontent in the vial. In some embodiments, the nitrogen flow rate isabout 20 liters per minute (L/min) to about 80 L/min. In someembodiments, the nitrogen flow rate is about 40 L/min to 60 L/min. Insome embodiments, the nitrogen flow rate is about 50 L/min.

In some embodiments, the improvement in the oxygen reduction devicefurther comprises adjusting a speed of a capping of the vial, such aswith a nasal spray system. In some embodiments, the capping rate isselected to permit purging of from about 100 vials per minute to about210 vials per minute. In some embodiments, the capping rate is about 150vials per minute to about 210 vials per minute. In some embodiments, thecapping rate is selected to permit purging of about 150 vials perminute. The adjustment of the speed of the capping may also compriseattaching a purging outlet 503 in FIG. 5 closer to the last stationwhere the capping of the vial takes place. By attaching the purgingoutlet 503 closer to the last station, the time lag between the vialleaving the assembly line and reaching the capping end can be reducedthereby reducing the amount of time the vial is exposed to air. In someembodiments, the nitrogen is blown into the vial simultaneously withcapping the vial. This improvement can further reduce the oxygen contentin the vial.

Provided herein is also a process to purge air from a vial, especiallyin an aseptic environment, the vial comprising a solution and a headspace, the process comprising: flowing an inert gas, such as nitrogen orargon, directly over and into the vial to purge the air out of the vialusing an improved oxygen reduction device wherein the device comprises atube with one or more purging outlets that flow the inert gas directlyover and into the vial to purge the air out of the vial, wherein theprocess reduces an oxygen content in the head space of the vial to equalto no more than about 10% v/v oxygen.

Provided herein is also a process to manufacture a nasal spray device,especially in an aseptic environment, the nasal spray device comprising:a vial and a nasal spray system capped to the vial wherein the vialcomprises a solution, a dip tube attached to the nasal spray system anddipping into the solution, and a head space above the solution, theprocess comprising:

a) providing the vial to an improved oxygen reduction device wherein theimproved oxygen reduction device comprises a tube with one or morepurging outlets that flow nitrogen directly over and into the vial topurge the air out of the vial;

b) flowing an inert gas, directly over and into the vial to purge theair out of the vial; and

c) capping the vial with a nasal spray system;

wherein the process reduces an oxygen content in the head space of thevial to equal to or less than about 10% v/v oxygen after the capping ofthe vial with the nasal spray system.

In some embodiments, the inert gas is nitrogen. In some embodiments, theinert gas is a noble gas. In some embodiments, the inert gas is argon.In some embodiments, the rate of capping is selected to be fast enoughto ensure that minimal atmospheric change occurs in the vial betweencompletion of the purging and capping and slow enough to ensure that thepurging process is effective. In some embodiments, capping occurs withinabout 0.28 to 1 second after purging so as to provide for 60 to 210vials capped per minute; preferably within about 0.28 to 0.4 seconds(150 to 210 vials capped per minute).

In some embodiments, all or a selected number of the treated and cappedvials are passed through spectrometry analysis to measure the oxygencontent and/or further remove the vials with unacceptable oxygencontent.

Compositions Useful in the Invention

In some embodiments, the solution inside the vial is an intranasalformulation of ketorolac or a pharmaceutically acceptable salt thereof.In some embodiments, the bacterial load in the solution is less thanabout 100 colony forming units (CFU).

In some embodiments, the intranasal formulation comprises concentrationsof ketorolac, or a pharmaceutically acceptable salt, ranging from about12.5 to 38% weight to volume (w/v), for example about 15%, 20%, 25%,28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, or 38% w/v, based onthe final formulation.

In some embodiments, the intranasal formulation comprises:

(a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceuticallyacceptable salt thereof, and

(b) a pharmaceutically acceptable carrier.

In some embodiments, the composition further comprises a localanesthetics, such as lidocaine, or a pharmaceutically acceptable salt,ranging from about 4% to 10%, for example about 4%, 5%, 6%, 7%, 8%, 9%,or 10% w/v. As disclosed in US Patent Application Publication No.2009/0042968, which is incorporated herein by reference in its entirety,the addition of lidocaine to the 15% ketorolac composition has beenfound to provide unexpected advantageous synergistic effects. First, thecombination substantially reduces the stinging sensation caused byketorolac. Second, while lidocaine is a local anesthetic that is knownto cause numbness, such numbness is substantially absent or reduced whenlidocaine is combined with ketorolac. Third, combination of 5 to 6% oflidocaine with ketorolac have been found to decrease the Tmax forketorolac to reach its Cmax in a subject's plasma, providing a subjectwith faster and better pain relief. It is contemplated that when theconcentration of ketorolac is increased to up to about 38%, the amountof lidocaine can be maintained at a level of 4-10% or preferably 5-6%and yet still inhibits the stinging sensation of ketorolac.

In some embodiments, the intranasal formulation comprises:

(a) about 12.5% w/v to about 38% w/v of ketorolac or a pharmaceuticallyacceptable salt thereof,

(b) about 4% w/v to about 10% w/v of lidocaine or a pharmaceuticallyacceptable salt thereof, and

(c) a pharmaceutically acceptable carrier.

In some embodiments, ketorolac is as a racemic mixture. In someembodiments, the pharmaceutically acceptable salt of ketorolac isketorolac tromethamine. In some embodiments, the intranasal formulationcomprises about 13% to 20% w/v of ketorolac tromethamine. In someembodiments, the intranasal formulation comprises about 15% w/v ofketorolac tromethamine. In some embodiments, the intranasal formulationcomprises about 25% to 35% w/v of ketorolac tromethamine. In someembodiments, the intranasal formulation comprises about 28% to 32% w/vof ketorolac tromethamine. In some embodiments, the intranasalformulation comprises about 30% w/v of ketorolac tromethamine.

In some embodiments, the intranasal formulation comprises lidocainehydrochloride. In some embodiments, the intranasal formulation comprisesabout 5-6% lidocaine hydrochloride. In some embodiments, the intranasalformulation comprises about 6% lidocaine hydrochloride.

In some embodiments, the intranasal formulation further comprises achelator, i.e. a substance that binds primarily di- or tri valentmetallic ions (e.g. calcium) that might interfere with the stability oractivity of the active ingredient. Chelators are known to those of skillin the art by referring to the recent edition of “Remington'sPharmaceutical Sciences.” A preferred chelator is sodium ethylenediaminetetraacetic acid (sodium EDTA), USP. In some embodiments, the chelatoris disodium edetate.

In some embodiments, the pH of the intranasal formulation is about 4.5to 8. In some embodiments, the pH is about 4.8 to 7.5. In someembodiments, the pH is about 7.2.

In some embodiments, the pH is adjusted by a pharmaceutically acceptablebase. In some embodiments, the pharmaceutically acceptable base issodium hydroxide.

A pharmaceutically acceptable buffer may be present in order to createoptimum pH conditions for both product stability and tolerance (pH rangeabout 4 to about 8; preferably about 6.0 to 7.5). Suitable buffersinclude without limitation tris(tromethamine) buffer, phosphate buffer,etc. Preferably potassium phosphate NF is used to adjust the pH to 7.2.In some embodiments, the composition comprises up to about 2% of aphosphate buffer, such as potassium phosphate monobasic, potassiumphosphate dibasic. In some embodiments, the composition comprises about0.6 to 0.8% w/v of potassium phosphate monobasic. In some embodiments,the composition comprises about 0.68% w/v of potassium phosphatemonobasic.

In some embodiments, the intranasal formulation is a sprayable liquid.

In some embodiments, the pharmaceutically acceptable carrier is water.

In some embodiments, the intranasal formulation comprises:

(a) about 15% w/v of racemic ketorolac tromethamine,

(b) about 0.01% w/v to about 0.1% w/v of disodium edetate,

(c) about 0.68% w/v of potassium phosphate monobasic,

(d) sodium hydroxide to adjust the pH to 7.2, and

(e) water to 100% w/v.

In some embodiments, the intranasal formulation comprises:

(a) about 15% w/v of racemic ketorolac tromethamine,

(b) about 5% w/v to about 6% w/v lidocaine hydrochloride,

(c) about 0.01% w/v to about 0.1% w/v of disodium edetate,

(d) about 0.68% w/v of potassium phosphate monobasic,

(e) sodium hydroxide to adjust the pH to 7.2, and

(f) water to 100% w/v.

In some embodiments, the intranasal formulation comprises:

(a) about 30% w/v of racemic ketorolac tromethamine,

(b) about 0.01% w/v to about 0.1% w/v of disodium edetate,

(c) about 0.68% w/v of potassium phosphate monobasic,

(d) sodium hydroxide to adjust the pH to 7.2, and

(e) water to 100% w/v.

In some embodiments, the intranasal formulation comprises:

(a) about 30% w/v of racemic ketorolac tromethamine,

(b) about 5% w/v to about 6% w/v lidocaine hydrochloride,

(c) about 0.01% w/v to about 0.1% w/v of disodium edetate,

(d) about 0.68% w/v of potassium phosphate monobasic,

(e) sodium hydroxide to adjust the pH to 7.2, and

(f) water to 100% w/v.

The intranasal formulation may optionally comprise one or morepharmaceutically acceptable excipients. The preferred diluent for theformulations is water, and other excipients may be added if desired.

In addition to aqueous, oil or gel diluents, other diluents which may beused in the intranasal formulation comprise solvent systems containingethyl alcohol, isopropyl alcohol, propylene glycol, polyethylene glycol,mixtures thereof or mixtures of one or more of the foregoing with water.

Other excipients include chemical enhancers such as absorptionpromoters. These include fatty acids, bile acid salts and othersurfactants, fusidic acid, lysophosphatides, cyclic peptide antibiotics,preservatives, carboxylic acids (ascorbic acid, amino acids),glycyrrhetinic acid, o-acylcarnitine. Preferred promoters arediisopropyladipate, POE(9) lauryl alcohol, sodium glycocholate andlysophosphatidyl choline which proved to be particularly active.

If present, excipients such as oil, gel, chemical enhancers, includingabosorption promoters, etc. should be in an amount that does notadversely affect the homogeneity and sprayability of the solution.

The intranasal formulation can also contain a compatible preservativethat ensures the microbiological stability of the active ingredient.Suitable preservatives include without limitation, methylparaoxybenzoate (methyl paraben), propyl paraoxybenzoate (propylparaben), sodium benzoate, benzyl alcohol, and chlorobutanol. In oneembodiment, the intranasal ketorolac formulation does not contain apreservative.

Illustrative formulations may contain the following ingredients andamounts (w/v) in addition to ketorolac, lidocaine and water.

Ingredient Broad Range (%) Preferred Range (%) Chelator (1) 0.001-1   0.01-0.1  Preservative (2) 0-2   0-0.25 Absorption promoter (3)  0-10 0-10 Gelling polymer (4) 0-5 0-3 Co-solvent (5)  0-99 0 (1) E.g.,sodium EDTA (2) E.g., methyl paraoxybenzoate or propyl paraoxybenzoateor mixtures thereof (3) E.g., sodium glycocholate (4) E.g., sodium CMC(5) E.g., glycerol

The following examples are provided to illustrate certain aspects of thepresent invention and to aid those of skill in the art in practicing theinvention. The examples are in no way to be considered to limit thescope of the invention.

EXAMPLE Example 1 Headspace Oxygen Analysis

Headspace oxygen concentrations were measured using a LighthouseInstruments FMS-760 Headspace Oxygen Analyzer. The measurements weremade to assess the performance of a nondestructive measurement methodfor headspace oxygen analysis.

Instrumentation and Method Laser Absorption Spectroscopy:

Laser absorption spectroscopy is an optical measurement method for rapidand non-invasive headspace gas analysis of containers, such asparenteral containers or containers for intranasal spray. The techniquecan measure a number of physical parameters within the headspace of thecontainer, including gas concentrations and total headspace pressures.

Light from a near-infrared semiconductor laser is tuned to match theinternal vibrational frequency of the target molecule. The light ispassed through the headspace region of a container, scanned in frequencyand detected by a photodetector. The amount of light absorbed isproportional to the target molecule concentration.

The instruments incorporate a high sensitivity detection method known asfrequency modulation spectroscopy.

Oxygen Absorption Spectroscopy: General

Oxygen absorbs near infrared light in a band of transitions centered at0.762 μm. The oxygen A-band is a series of rotational transitions withinthe 0-0 vibrational band of the X³Σ⁻ _(g)←b¹Σ⁺ _(g) magnetic dipoletransition.

Headspace Oxygen Measurements Measurement Principle

The amount of laser light absorbed by an individual transition in theoxygen A-band is proportional to the oxygen concentration in theheadspace of a parenteral or nasal spray container. In general the laserfrequency is repeatedly scanned over the absorption feature andsuccessive scans are averaged to improve the signal to noise ratio. Theaveraged light absorption signal (an example shown in FIG. 6) and thetotal power are then multiplied by a calibration constant to yield theheadspace oxygen concentration.

Instrument Calibration

An instrument calibration constant, k, is determined using a vial filledwith a known concentration of oxygen. Oxygen standards are preparedusing certified gas mixtures of oxygen and nitrogen. A 20% oxygen/80%nitrogen standard is used for FMS-760 calibration.

A calibration standard is inserted to the instrument, the systemresponse (signal amplitude, S, and power, P) is measured and acalibration constant is computed.

The instrument calibration procedure is fully automated and controlledby the instrument computer. Once the user inputs the calibration vialand initiates the calibration routine the instrument begins to recorddata and using the known concentration computes a calibration constantk,

k=(P/S)·Known Concentration  [1]

where P is the detected laser power, S is the peak to peak absorptionsignal (see FIG. 6 for oxygen example), and Known Concentration is theconcentration in the calibration vial. The measured values of P and Sare the average of 1000 scans (10 s acquisition time). The system storesthe calibration constant and uses it for subsequent sample measurements.

Measurements

The instrument data acquisition system uses the stored calibrationconstant to determine the headspace oxygen concentration in a sample.When a sample with an unknown concentration is inserted to an instrumentthe system measures the absorption signal and laser power and multipliesby the calibration constant to determine the headspace oxygen or watervapor concentration.

$\begin{matrix}{{\% \mspace{14mu} {Oxygen}\mspace{14mu} {in}\mspace{14mu} {Sample}} = {\left( {S_{m}/P_{m}} \right) \cdot {k\mspace{385mu}\lbrack 2\rbrack}}} \\{= {{\left( {S_{m}/P_{m}} \right) \cdot \left( {P_{c}/S_{c}} \right) \cdot \%}\mspace{14mu} {Oxygen}\mspace{14mu} {in}\mspace{14mu} {{Standard}\mspace{56mu}\lbrack 3\rbrack}}}\end{matrix}$

where S_(m) is the sample signal amplitude, P_(m) is the laser powertransmitted through the sample, P_(c) is the calibration power and S_(c)is the calibration signal amplitude, % Oxygen in Standard is the knownamount of oxygen in the calibration vial.

Measurement Protocol

Headspace oxygen measurements were performed using a LighthouseInstruments FMS-760 Headspace Oxygen Analyzer (SN 760-104). Theinstrument was turned on and allowed to warm up for thirty minutes.Calibration was performed using a 21% oxygen standard. The headspaceoxygen concentration in each sample was measured three times.

Example 2 Reduction of Oxygen Content in the Head Space of a Vial

A suitable length of a tubing, preferably made of a chemical resistantpolymer and preferably free from contamination, is connected to an argonor nitrogen gas tank at one end. The other end of the tubing is insertedin the mouth of a vial having a ketorolac solution and an about 2 mLhead space, preferably the tubing does not touch the ketorolac solutioninside the vial. Argon or nitrogen is passed through the tubing into thevial for a sufficient amount of time so that the oxygen content in thehead space of the vial is less than 10%. The tubing is removed from thevial and the vial is capped with a nasal spray system and stored at roomtemperature.

Example 3 Oxygen Content in the Head Space of Vials Purged by aConventional Oxygen Reduction Device in an Assembly Line

Vials were processed using a conventional oxygen reduction device havinga tube with purging holes. Other conditions are the same as described inExample 4 below. The oxygen content of the following five sets of glassvials were tested using the above described protocol of Example 1. Theindividual results were recorded and averaged and mean concentration andstandard deviation were computed. The results of the samples tested aresummarized below.

Set 1: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solutionwith Nitrogen Overlay

The individual headspace oxygen measurements of the five samples variedfrom between 17.8% to 20.5%, and the average headspace oxygenconcentrations of the each of the five samples varied between 18.3% and20.2%, with a mean of 19.0% and a standard deviation of 0.80%.

Set 2: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solutionwithout Nitrogen Overlay

The individual headspace oxygen measurements of the five samples variedfrom between 20.2% to 21.7%, and the average headspace oxygenconcentrations of each of the five samples varied between 20.6% and21.1%, with a mean of 20.8% and a standard deviation of 0.20%.

Set 3: Five 4 mL Clear Glass Vials Containing a 2 mL Fill of Solutionwith Nitrogen Overlay

Set 3 is a repeat of Set 1, except that in Set 3 the samples werecollected after stopping the capper (simulated line stoppage) for 5minutes and resuming the capping operation.

The individual headspace oxygen measurements of the five samples variedfrom between 18.2% to 22.0%, and the average headspace oxygenconcentrations of each of the five samples varied between 18.7% and21.4%, with a mean of 19.5% and a standard deviation of 1.11%.

Set 4: Five Empty 4 mL Clear Glass Vials with Nitrogen Overlay

The individual headspace oxygen measurements of the five samples variedfrom between 20.5% to 21.9%, and the average headspace oxygenconcentrations of each of the five samples varied between 18.4% and21.8%, with a mean of 19.9% and a standard deviation of 1.46%.

Set 5: Five Empty 4 mL Clear Glass Vials without Nitrogen Overlay

The individual headspace oxygen measurements of the five samples variedfrom between 18.1% to 21.7%, and the average headspace oxygenconcentrations of each of the five samples varied between 21.1% and21.4%, with a mean of 21.3% and a standard deviation of 0.12%.

Example 4 Oxygen Content in the Head Space of Vials Purged by anImproved Oxygen Reduction Device

This experiment was conducted to determine optimal nitrogen flow atcapping rates of 150 and 210 vials per minute utilizing an improvedoxygen reduction device of this invention. Further engineering changeswithin the skill in the art can be applied to generate commercial ormanufacture devices.

The experiment was conducted using 20 mm Hi-Recovery vials (4 mL) andsnap-on metering pump. The vials were filled with about 1.8 mL ofinjection quality water (WFI) while purged with nitrogen having varyingflow rates. The experiment was repeated with a similar oxygen reductiondevice having GMP quality. Twenty vials from each fill speed and flowrate combination were sampled and tested. Result summaries are shown inthe following tables 1 and 2.

TABLE 1 150 Vials per Minute - Results in % O₂ (v/v) 0 L/min 20 L/min 40L/min 60 L/min 80 L/min Average* 20.49 9.53 6.89 6.69 6.78 Minimum**19.83 8.49 6.10 5.25 5.42 Maximum*** 21.17 12.45 9.52 9.22 10.27

TABLE 2 210 Vials per Minute - Results in % O₂ (v/v) 0 L/min 20 L/min 40L/min 60 L/min 80 L/min Average* 20.60 11.03 9.23 7.49 8.14 Minimum**19.99 8.01 6.99 6.29 6.66 Maximum*** 21.57 13.66 19.29 13.42 17.03* “Average” indicates the average O₂ content in the tested vials for therespective group.** “Minimum” indicates the O₂ content of the vial with the lowest O₂content in the respective group.*** “Maximum” indicates the O₂ content of the vial with the highest O₂content in the respective group.

The data show all vials prepared using the 150 vials per minute rate hadan oxygen content of less than 13% and all vials prepared with flowrates at 40 and 60 L/min had an oxygen content of below the 10%.

The data show that the capping rate is one of the critical parameters inensuring that the head space of the vials maintains an oxygenconcentration of 10% v/v or less. The results indicate that oxygencontents for the vials run at 150 vials per minute were generally lowerthan the same settings at 210 vials per minute. It is contemplated thatcapping speeds would directly affect the amount of retention time eachvial has under the oxygen reduction device bar nozzles. In addition, atthe high machine speed (210 vials per minute), frequent pauses wereobserved as the pump bowl was not supplying pumps at the same rate. Thismay have caused the high oxygen contents in some of the vials preparedat a rate of 210 vials per minute. It is anticipated that adjustedoperation of the pump bowl would reduce the frequency and duration ofthe pauses, which would result in tighter oxygen level results. Anothersolution is to reject vials after machine stoppage.

Residual oxygen contents for 80 L/min at both speeds were slightlyhigher than those observed at the 60 L/min flow. As flow rate getshigher, the volume that can be displaced is higher, but the flow alsogrows more turbulent, possibly entraining ambient air with the purgeair.

It is to be understood that while the invention has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains.

1.-37. (canceled)
 38. A drug delivery system for intranasaladministration of ketorolac or a pharmaceutically acceptable saltthereof, comprising a vial having a cap and a spray system, wherein thevial has a concave or V-shaped inner bottom, the vial has a volumebetween the cap and inner bottom of 10 mL or less and contains asolution comprising ketorolac or a pharmaceutically acceptable saltthereof, the vial comprises a dip tube attached to the spray system,wherein the dip tube dips into the solution and an end of the dip tubeis proximate to a bottommost portion of the inner bottom, and a headspace defined by the space between a top surface of the solution and thecap comprises less than 10% v/v oxygen.
 39. The drug delivery system ofclaim 38, wherein the head space comprises no more than 80% of thevolume of the vial.
 40. The drug delivery system of claim 38, whereinthe solution comprises from about 12.5% w/v to about 38% w/v ofketorolac tromethamine.
 41. The drug delivery system of claim 38,wherein the solution comprises from about 13% w/v to about 20% w/v ofketorolac tromethamine.
 42. The drug delivery system of claim 38,wherein the solution comprises about 15% w/v of ketorolac tromethamine.43. The drug delivery system of claim 38, wherein the solution comprisesabout 30% w/v of ketorolac tromethamine.
 44. The drug delivery system ofclaim 38, wherein the solution further comprises about 4% to about 10%w/v lidocaine hydrochloride.
 45. The drug delivery system of claim 38,wherein the solution is stable when stored in the vial at roomtemperatures for two years or more.
 46. The drug delivery system ofclaim 38, wherein the dip tube is notched.
 47. A method foradministering a solution comprising ketorolac or a pharmaceuticallyacceptable salt thereof, comprising intranasally administering thesolution from a drug delivery system according to claim
 38. 48. Themethod of claim 47, wherein the solution is administered to treat painor inflammation in a subject in need thereof.